Nonpeptide Angiotensin II Receptor Antagonists:  Synthesis, Biological Activities, and Structure−Activity Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds

Yanagisawa, Hideyoshi; Amemiya, Yoshiya; Kanazaki, Takuro; Shimoji, Yasuo; Fujimoto, Koichi; Kitahara, Yoshiko; Sada, Toshio; Mizuno, Makoto; Ikeda, Masahiro; Miyamoto, Shuichi; Furukawa, Y.; Koike, Hiroyuki

doi:10.1021/jm950450f

Cited by 133 publications

(62 citation statements)

References 46 publications

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“…AZL was synthesized in Takeda Pharmaceutical Company Limited (Osaka, Japan). Olmesartan (Yanagisawa et al, 1996), telmisartan (Ries et al, 1993), valsartan (Bü hlmayer et al, 1994), and irbesartan (Bernhart et al, 1993) were used in this experiment as competitors. Olmesartan was prepared from olmesartan medoxomil (Daiichi-Sankyo, Tokyo, Japan).…”

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confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

140

115

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The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2Ј-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of 125 I-Sar 1 -Ile 8 -AII to human angiotensin type 1 receptors with an IC 50 of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC 50 value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC 50 values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC 50 values of 242.5, 191.6, Ͼ10,000, and Ͼ10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC 50 value of 9.2 nmol; this effect was resistant to washout (IC 50 value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC 50 values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC 50 value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pDЈ 2 value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.

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Section: Downloaded Frommentioning

confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

140

115

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“…4,5,6 Although several previous studies have compared the antihypertensive efficacy of ARBs on the basis of cuff blood pressure change, such comparisons have largely been against losartan only. 7 Losartan is the first drug to be marketed within the ARB class and has been shown to be relatively ineffective for 24-hour control of blood pressure.…”

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confidence: 99%

Comparative Efficacy and Safety of Olmesartan Versus Losartan in Patients With Hypertension

Mujeeb¹,

Jalikar²

2015

jemds

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Angiotensin II receptor blockers (ARBs) are the newest class of approved antihypertensive agents and the second class of drugs to exert their primary antihypertensive action by interrupting the renin-angiotensin system. It was a multicenter, randomized, double-blind trial in which efficacy of Olmesartan (20mg once a day) and losartan (50mg once a day) was compared in patients with hypertension. In patients with a cuff diastolic blood pressure (DBP) of ≥100 and ≥115 mm Hg and a mean daytime DBP of ≥90mm Hg and <120mm Hg, as measured by ambulatory blood pressure monitoring. Cuff and ambulatory blood pressures were monitored at baseline and after 8 weeks of treatment. All groups were adults and approximately 62% male, and their mean age was approximately 52 years. In all groups, mean baseline DBP and systolic blood pressure (SBP) were approximately 104 and 157mm Hg, respectively. The reduction of sitting cuff DBP with olmesartan (13.5mm Hg), the primary efficacy variable of this study, was significantly greater than with losartan, enalapril, and quinapril (8.2, 7.9, and 9.9mm Hg, respectively). Reductions of cuff SBP with the four ARBs ranged from 8.4-13.3mm Hg and were not significantly different. The reduction in mean 24-hour DBP with olmesartan (8.5mm Hg) was significantly greater than reductions with losartan and enalapril (6.2 and 5.6mm Hg, respectively) and showed a trend toward significance when compared to the reduction in DBP with quinapril (7.4mm Hg; p=0.087). The reduction in mean 24-hour SBP with olmesartan (12.5mm Hg) was significantly greater than the reductions with losartan and enalapril (9.0 and 8.1mm Hg, respectively) and equivalent to the reduction with quinapril (11.3mm Hg). All drugs were well tolerated. The authors conclude that olmesartan, at its starting dose, is more effective than the starting doses of the other tested drugs in reducing cuff DBP in patients with essential hypertension. KEYWORDS: Essential Hypertension, Enalapril, Losartan, Olmesartan. INTRODUCTION:Angiotensin II receptor blockers (ARBs) are the newest class of approved antihypertensive agents and the second class of drugs to exert their primary antihypertensive action by interrupting the renin-angiotensin system. ARBs prevent the hypertensive effects of angiotensin II by selective blockade of the angiotensin II type 1 (AT1) receptor. Olmesartan is a new ARB that was discovered during a systematic survey of the AT1 binding actions of substituted imidazole-5-carboxylic acids.It is a prodrug that, following oral administration, is rapidly and completely de-esterified in the gut to its active form, in a reaction that is not cytochrome P-450-dependent. This active metabolite, olmesartan, is a potent and selective AT1 receptor antagonist, with no agonist activity. 1,2,3 In healthy subjects, olmesartan has an elimination half-life of 12-18 hours, a value that is comparable to the longest half-lives of ARBs currently in clinical use.

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“…OLM Medoxomil is a pro-drug and is hydrolyzed to OLM during absorption from the gastrointestinal tract (Yanagisawa et al 1996;Mire et al 2005). OLM is described chemically as the (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{ [20-(1H-tetrazol-5-yl)[1,10-biphenyl]-4-yl]methyl}-1H-imidazole-5-carboxylic acid.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Determination of Amlodipine and Olmesartan in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry and Its Application in Pharmacokinetic Study

Jain¹,

YR²,

Kishore³

2016

Bull. Pharm. Res

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The present study describes a sensitive, specific and rapid method based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of amlodipine (AML) and olmesartan (OLM) in human plasma by using amlodipine D4 (IS1) and olmesartan D6 (IS2) as internal standards. Plasma samples were extracted by solid-phase extraction (SPE). The method was validated over parameters like selectivity, matrix effect, sensitivity, specificity, linearity, precision and accuracy, various stabilities in plasma, recovery and reinjection reproducibility. During the validation, inter and intra-batch precision were less than 15% and the accuracy was within 85-115%. Extraction recoveries were 75.30%, 81.41%, 79.19% and 81.72% for AML, OLM, IS1 and IS2 respectively. The method was applied to the pharmacokinetic study of OLM and AML in healthy subjects following a single oral dose of OLM and AML 40 mg/10 mg.

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Nonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure−Activity Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds

Cited by 133 publications

References 46 publications

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Comparative Efficacy and Safety of Olmesartan Versus Losartan in Patients With Hypertension

Simultaneous Determination of Amlodipine and Olmesartan in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry and Its Application in Pharmacokinetic Study

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